Given the critical importance of chemical synaptic transmission in normal and pathological neural activity, intensive investigation of the underlying mechanisms has long been and remains a primary focus in molecular and cellular neuroscience. Greater understanding of the molecular mechanisms of synaptic transmission will be of tremendous value in defining neurological disease processes and developing rational therapies to combat them. The proposed studies build on our recent genetic analysis in Drosophila implicating the DISABLED (DAB) proteins in the synaptic vesicle endocytosis - the process which recycles neurotransmitter filled secretory vesicles after they fuse with the surface membrane and release their contents. In part because DABs are known to play critical roles in sorting surface membrane proteins and have been implicated in major human health conditions including cardiovascular disease, it is exciting to consider another role for these proteins and their molecular mechanisms in synaptic transmission. A function for DABs in sorting synaptic vesicle proteins has not been identified previously, however the proposed studies may now reveal an important synaptic connection for an already intensively studied set of DAB-dependent mechanisms. This project will (1) build on genetic analysis implicating a novel DAB-related mechanism in synaptic transmission to define the functional role of dDAB in the critical process of synaptic vesicle endocytosis and (2) examine the connections between a new function for DAB proteins and previously characterized mechanisms of synaptic vesicle endocytosis to gain a better understanding of the organization and molecular interactions underlying chemical synaptic transmission. PUBLIC HEALTH RELEVANCE: Given the critical importance of chemical synaptic transmission in normal and pathological neural activity, greater understanding of the molecular mechanisms of synaptic transmission will be of tremendous value in defining neurological disease processes and developing rational therapies to combat them. The proposed studies are building on exciting discoveries through genetics that are implicating specific genes and proteins and promise to provide new insights into the process of chemical synaptic transmission.